New drug for schizophrenia could meet desperate need for better treatments
Schizophrenia is a debilitating mental health condition that affects around 24 million people worldwide. Patients experience hallucinations and delusions when they develop schizophrenia, with experts referring to these new thoughts and behaviors as positive symptoms. They also suffer from negative symptoms in which they lose important functions, suffering from dulled emotions, lack of purpose and social withdrawal.
Currently available drugs can control only a portion of these symptoms but, on August 8th, Karuna Therapeutics announced its completion of a phase 3 clinical trial that found a new drug called KarXT could treat both positive and negative symptoms of schizophrenia. It could mean substantial progress against a problem that has stymied scientists for decades.
A long-standing problem
Since the 1950s, antipsychotics have been used to treat schizophrenia. People who suffer from it are thought to have too much of a brain chemical called dopamine, and antipsychotics work by blocking dopamine receptors in the brain. They can be effective in treating positive symptoms but have little impact on the negative ones, which can be devastating for a patient’s quality of life, making it difficult to maintain employment and have successful relationships. About 30 percent of schizophrenia patients don't actually respond to antipsychotics at all. Current drugs can also have adverse side effects including elevated cholesterol, high blood pressure, diabetes and movements that patients cannot control.
The recent clinical trial heralds a new treatment approach. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” says Andrew Miller, COO of Karuna.
Scientists have been looking to develop alternatives. However, “the field of drug treatment of schizophrenia is currently in the doldrums,” says Peter McKenna, a senior researcher at FIDMAG Research Foundation in Spain which specialises in mental health.
In the 2000s there was a major push to target a brain receptor for a chemical called glutamate. Evidence suggested that this receptor is abnormal in the brains of schizophrenia patients, but attempts to try glutamate failed in clinical trials.
After that, many pharmaceutical companies dropped out of the race for a more useful treatment. But some companies continued to search, such as Karuna Therapeutics, led by founder and Chief Operating Officer Andrew Miller and CEO Steve Paul. The recent clinical trial suggests their persistence has led to an important breakthrough with their drug, KarXT. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” Miller says.
How it works
Neurotransmitters are chemical messengers that pass signals between neurons. To work effectively, neurotransmitters need a receptor to bind to. A neurotransmitter called acetylcholine seems to be especially important in schizophrenia. It interacts with sites called muscarinic receptors, which are involved in the network of nerves that calm your body after a stressful event. Post mortem studies in people with schizophrenia have shown that two muscarinic receptors in the brain, the M1 and M4 receptors, are activated at unusually low levels because they don’t receive enough signals from acetylcholine.
The M4 receptor appears to play a role in psychosis. The M1 receptor is also associated with psychosis but is primarily thought to be involved in cognition. KarXT, taken orally, works by activating both of these receptors to signal properly. It is this twofold action that seems to explain its effectiveness. “[The drug’s] design enables the preferential stimulation of these muscarinic receptors in the brain,” Miller says.
How it developed
It all started in the early 1990s when Paul was at pharmaceutical company Eli Lilly. He discovered that Xanomeline, the drug they were testing on Alzheimer's patients, had antipsychotic effects. It worked by stimulating M1 and M4 receptors, so he and his colleagues decided to test Xanomeline on schizophrenia patients, supported by research on the connection between muscarinic receptors and psychosis. They found that Xanomeline reduced both positive and negative symptoms.
Unfortunately, it also caused significant side effects. The problem was that stimulating the M1 and M4 receptors in the brain also stimulated muscarinic receptors in the body that led to severe vomiting, diarrhea and even the temporary loss of consciousness.
In the end, Eli Lilly discontinued the clinical trials for the drug, but Miller set up Karuna Therapeutics to develop a solution. “I was determined to find a way to harness the therapeutic benefit demonstrated in studies of Xanomeline, while eliminating side effects that limited its development,” Miller says.
He analysed over 7,000 possible ways of mixing Xanomeline with other agents before settling on KarXT. It combines Xanomeline with a drug called Trospium Chloride, which blocks muscarinic receptors in the body – taking care of the side effects such as vomiting – but leaves them unblocked in the brain. Paul was so excited by Miller’s progress that he joined Karuna after leaving Eli Lilly and founding two previous startups.
“It's a very important approach,” says Rick Adams, Future Leaders Fellow in the Institute of Cognitive Neuroscience and Centre for Medical Image Computing at University College London. “We are in desperate need of alternative drug targets and this target is one of the best. There are other alternative targets, but not many are as close to being successful as the muscarinic receptor drug.”
Clinical Trial
Following a successful phase 2 clinical trial in 2019, the most recent trial involved 126 patients who were given KarXT, and 126 who were given a placebo. Compared to the placebo, patients taking KarXT had a significant 9.6 point reduction in the positive and negative syndrome scale (PANSS), the standard for rating schizophrenic symptoms.
KarXT also led to statistically significant declines in positive and negative symptoms compared to the placebo. “The results suggest that KarXT could be a potentially game-changing option in the management of both positive and negative symptoms of schizophrenia,” Miller says.
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, is optimistic about the side effects but highlights the need for more safety trials.
McKenna, the researcher at FIDMAG Foundation, agrees about the drug’s potential. “The new [phase 3] study is positive,” he says. “It is reassuring that one is not dealing with a drug that works in one trial and then inexplicably fails in the next one.”
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, said the drug is an unprecedented step forward. “KarXT is one of the first drugs with a novel mechanism of action to show promise in clinical trials.”
Even though the drug blocks muscarine receptors in the body, some patients still suffered from adverse side effects like vomiting, dizziness and diarrhea. But in general, these effects were mild to moderate, especially compared to dopamine-blocking antipsychotics or Xanomeline on its own.
McCutcheon is optimistic about the side effects but highlights the need for more safety trials. “The trial results suggest that gastrointestinal side effects appear to be manageable,” he says. “We know, however, from previous antipsychotic drugs that the full picture regarding the extent of side effects can sometimes take longer to become apparent to clinicians and patients. Careful ongoing assessment during a longer period of treatment will therefore be important.”
The Future
The team is currently conducting three other trials to evaluate the efficacy and long-term safety of KarXT. Their goal is to receive FDA approval next year.
Karuna is also conducting trials to evaluate the effectiveness of KarXT in treating psychosis in patients suffering from Alzheimer’s.
The big hope is that they will soon be able to provide a radically different drug to help many patients with schizophrenia. “We are another step closer to potentially providing the first new class of medicine in more than 50 years to the millions of people worldwide living with schizophrenia,” says Miller.
Hours after a baby is born, its heel is pricked with a lancet. Drops of the infant's blood are collected on a porous card, which is then mailed to a state laboratory. The dried blood spots are screened for around thirty conditions, including phenylketonuria (PKU), the metabolic disorder that kick-started this kind of newborn screening over 60 years ago. In the U.S., parents are not asked for permission to screen their child. Newborn screening programs are public health programs, and the assumption is that no good parent would refuse a screening test that could identify a serious yet treatable condition in their baby.
Learning as much as you can about your child's health might seem like a natural obligation of parenting. But it's an assumption that I think needs to be much more closely examined.
Today, with the introduction of genome sequencing into clinical medicine, some are asking whether newborn screening goes far enough. As the cost of sequencing falls, should parents take a more expansive look at their children's health, learning not just whether they have a rare but treatable childhood condition, but also whether they are at risk for untreatable conditions or for diseases that, if they occur at all, will strike only in adulthood? Should genome sequencing be a part of every newborn's care?
It's an idea that appeals to Anne Wojcicki, the founder and CEO of the direct-to-consumer genetic testing company 23andMe, who in a 2016 interview with The Guardian newspaper predicted that having newborns tested would soon be considered standard practice—"as critical as testing your cholesterol"—and a new responsibility of parenting. Wojcicki isn't the only one excited to see everyone's genes examined at birth. Francis Collins, director of the National Institutes of Health and perhaps the most prominent advocate of genomics in the United States, has written that he is "almost certain … that whole-genome sequencing will become part of new-born screening in the next few years." Whether that would happen through state-mandated screening programs, or as part of routine pediatric care—or perhaps as a direct-to-consumer service that parents purchase at birth or receive as a baby-shower gift—is not clear.
Learning as much as you can about your child's health might seem like a natural obligation of parenting. But it's an assumption that I think needs to be much more closely examined, both because the results that genome sequencing can return are more complex and more uncertain than one might expect, and because parents are not actually responsible for their child's lifelong health and well-being.
What is a parent supposed to do about such a risk except worry?
Existing newborn screening tests look for the presence of rare conditions that, if identified early in life, before the child shows any symptoms, can be effectively treated. Sequencing could identify many of these same kinds of conditions (and it might be a good tool if it could be targeted to those conditions alone), but it would also identify gene variants that confer an increased risk rather than a certainty of disease. Occasionally that increased risk will be significant. About 12 percent of women in the general population will develop breast cancer during their lives, while those who have a harmful BRCA1 or BRCA2 gene variant have around a 70 percent chance of developing the disease. But for many—perhaps most—conditions, the increased risk associated with a particular gene variant will be very small. Researchers have identified over 600 genes that appear to be associated with schizophrenia, for example, but any one of those confers only a tiny increase in risk for the disorder. What is a parent supposed to do about such a risk except worry?
Sequencing results are uncertain in other important ways as well. While we now have the ability to map the genome—to create a read-out of the pairs of genetic letters that make up a person's DNA—we are still learning what most of it means for a person's health and well-being. Researchers even have a name for gene variants they think might be associated with a disease or disorder, but for which they don't have enough evidence to be sure. They are called "variants of unknown (or uncertain) significance (VUS), and they pop up in most people's sequencing results. In cancer genetics, where much research has been done, about 1 in 5 gene variants are reclassified over time. Most are downgraded, which means that a good number of VUS are eventually designated benign.
While one parent might reasonably decide to learn about their child's risk for a condition about which nothing can be done medically, a different, yet still thoroughly reasonable, parent might prefer to remain ignorant so that they can enjoy the time before their child is afflicted.
Then there's the puzzle of what to do about results that show increased risk or even certainty for a condition that we have no idea how to prevent. Some genomics advocates argue that even if a result is not "medically actionable," it might have "personal utility" because it allows parents to plan for their child's future needs, to enroll them in research, or to connect with other families whose children carry the same genetic marker.
Finding a certain gene variant in one child might inform parents' decisions about whether to have another—and if they do, about whether to use reproductive technologies or prenatal testing to select against that variant in a future child. I have no doubt that for some parents these personal utility arguments are persuasive, but notice how far we've now strayed from the serious yet treatable conditions that motivated governments to set up newborn screening programs, and to mandate such testing for all.
Which brings me to the other problem with the call for sequencing newborn babies: the idea that even if it's not what the law requires, it's what good parents should do. That idea is very compelling when we're talking about sequencing results that show a serious threat to the child's health, especially when interventions are available to prevent or treat that condition. But as I have shown, many sequencing results are not of this type.
While one parent might reasonably decide to learn about their child's risk for a condition about which nothing can be done medically, a different, yet still thoroughly reasonable, parent might prefer to remain ignorant so that they can enjoy the time before their child is afflicted. This parent might decide that the worry—and the hypervigilence it could inspire in them—is not in their child's best interest, or indeed in their own. This parent might also think that it should be up to the child, when he or she is older, to decide whether to learn about his or her risk for adult-onset conditions, especially given that many adults at high familial risk for conditions like Alzheimer's or Huntington's disease choose never to be tested. This parent will value the child's future autonomy and right not to know more than they value the chance to prepare for a health risk that won't strike the child until 40 or 50 years in the future.
Parents are not obligated to learn about their children's risk for a condition that cannot be prevented, has a small risk of occurring, or that would appear only in adulthood.
Contemporary understandings of parenting are famously demanding. We are asked to do everything within our power to advance our children's health and well-being—to act always in our children's best interests. Against that backdrop, the need to sequence every newborn baby's genome might seem obvious. But we should be skeptical. Many sequencing results are complex and uncertain. Parents are not obligated to learn about their children's risk for a condition that cannot be prevented, has a small risk of occurring, or that would appear only in adulthood. To suggest otherwise is to stretch parental responsibilities beyond the realm of childhood and beyond factors that parents can control.
The Brave New World of Using DNA to Store Data
Netscape co-founder-turned-venture capitalist billionaire investor Marc Andreessen once posited that software was eating the world. He was right, and the takeover of software resulted in many things. One of them is data. Lots and lots and lots of data. In the previous two years, humanity created more data than it did during its entire existence combined, and the amount will only increase. Think about it: The hundreds of 50KB emails you write a day, the dozens of 10MB photos, the minute-long, 350MB 4K video you shoot on your iPhone X add up to vast quantities of information. All that information needs to be stored. And that's becoming an issue as data volume outpaces storage space.
The race is on to find another medium capable of storing massive amounts of information in as small a space as possible.
"There won't be enough silicon to store all the data we need. It's unlikely that we can make flash memory smaller. We have reached the physical limits," Victor Zhirnov, chief scientist at the Semiconductor Research Corporation, says. "We are facing a crisis that's comparable to the oil crisis in the 1970s. By 2050, we're going to need to store 10 to the 30 bits, compared to 10 to the 23 bits in 2016." That amount of storage space is equivalent to each of the world's seven billion people owning almost six trillion -- that's 10 to the 12th power -- iPhone Xs with 256GB storage space.
The race is on to find another medium capable of storing massive amounts of information in as small a space as possible. Zhirnov and other scientists are looking at the human body, looking to DNA. "Nature has nailed it," Luis Ceze, a professor in the Department of Computer Science and Engineering at the University of Washington, says. "DNA is a molecular storage medium that is remarkable. It's incredibly dense, many, many thousands of times denser than the densest technology that we have today. And DNA is remarkably general. Any information you can map in bits you can store in DNA." It's so dense -- able to store a theoretical maximum of 215 petabytes (215 million gigabytes) in a single gram -- that all the data ever produced could be stored in the back of a tractor trailer truck.
Writing DNA can be an energy-efficient process, too. Consider how the human body is constantly writing and rewriting DNA, and does so on a couple thousand calories a day. And all it needs for storage is a cool, dark place, a significant energy savings when compared to server farms that require huge amounts of energy to run and even more energy to cool.
Picture it: tiny specks of inert DNA made from silicon or another material, stored in cool, dark, dry areas, preserved for all time.
Researchers first succeeded in encoding data onto DNA in 2012, when Harvard University geneticists George Church and Sri Kosuri wrote a 52,000-word book on A, C, G, and T base pairs. Their method only produced 1.28 petabytes per gram of DNA, however, a volume exceeded the next year when a group encoded all 154 Shakespeare sonnets and a 26-second clip of Martin Luther King's "I Have A Dream" speech. In 2017, Columbia University researchers Yaniv Erlich and Dina Zielinski made the process 60 percent more efficient.
The limiting factor today is cost. Erlich said the work his team did cost $7,000 to encode and decode two megabytes of data. To become useful in a widespread way, the price per megabyte needs to plummet. Even advocates concede this point. "Of course it is expensive," Zhirnov says. "But look how much magnetic storage cost in the 1980s. What you store today in your iPhone for virtually nothing would cost many millions of dollars in 1982." There's reason to think the price will continue to fall. Genome readers are improving, getting cheaper, faster, and smaller, and genome sequencing becomes cheaper every year, too. Picture it: tiny specks of inert DNA made from silicon or another material, stored in cool, dark, dry areas, preserved for all time.
"It just takes a few minutes to double a sample. A few more minutes, you double it again. Very quickly, you have thousands or millions of new copies."
Plus, DNA has another advantage over more traditional forms of storage: It's very easy to reproduce. "If you want a second copy of a hard disk drive, you need components for a disk drive, hook both drives up to a computer, and copy. That's a pain," Nick Goldman, a researcher at the European Bioinformatics Institute, says. "DNA, once you have that first sample, it's a process that is absolutely routine in thousands of laboratories around the world to multiply that using polymerase chain reaction [which uses temperature changes or other processes]. It just takes a few minutes to double a sample. A few more minutes, you double it again. Very quickly, you have thousands or millions of new copies."
This ability to duplicate quickly and easily is a positive trait. But, of course, there's also the potential for danger. Does encoding on DNA, the very basis for life, present ethical issues? Could it get out of control and fundamentally alter life as we know it?
The chance is there, but it's remote. The first reason is that storage could be done with only two base pairs, which would serve as replacements for the 0 and 1 digits that make up all digital data. While doing so would decrease the possible density of the storage, it would virtually eliminate the risk that the sequences would be compatible with life.
But even if scientists and researchers choose to use four base pairs, other safeguards are in place that will prevent trouble. According to Ceze, the computer science professor, the snippets of DNA that they write are very short, around 150 nucleotides. This includes the title, the information that's being encoded, and tags to help organize where the snippet should fall in the larger sequence. Furthermore, they generally avoid repeated letters, which dramatically reduces the chance that a protein could be synthesized from the snippet.
"In the future, we'll know enough about someone from a sample of their DNA that we could make a specific poison. That's the danger, not those of us who want to encode DNA for storage."
Inevitably, some DNA will get spilt. "But it's so unlikely that anything that gets created for storage would have a biological interpretation that could interfere with the mechanisms going on in a living organism that it doesn't worry me in the slightest," Goldman says. "We're not of concern for the people who are worried about the ethical issues of synthetic DNA. They are much more concerned about people deliberately engineering anthrax. In the future, we'll know enough about someone from a sample of their DNA that we could make a specific poison. That's the danger, not those of us who want to encode DNA for storage."
In the end, the reality of and risks surrounding encoding on DNA are the same as any scientific advancement: It's another system that is vulnerable to people with bad intentions but not one that is inherently unethical.
"Every human action has some ethical implications," Zhirnov says. "I can use a hammer to build a house or I can use it to harm another person. I don't see why DNA is in any way more or less ethical."
If that house can store all the knowledge in human history, it's worth learning how to build it.
Editor's Note: In response to readers' comments that silicon is one of the earth's most abundant materials, we reached back out to our source, Dr. Victor Zhirnov. He stands by his statement about a coming shortage of silicon, citing this research. The silicon oxide found in beach sand is unsuitable for semiconductors, he says, because the cost of purifying it would be prohibitive. For use in circuit-making, silicon must be refined to a purity of 99.9999999 percent. So the process begins by mining for pure quartz, which can only be found in relatively few places around the world.